Periodontitis is a disease that is characterized by regression of periodontal tissues and the loss of alveolar bone that surround the tooth root surface. It is likely that both host and bacterial factors contribute to tissue and bone destruction. Porphyromonas gingivalis, a gram negative bacterium, has been identified as an etiological agent of disease however its role in the disease process is not yet fully understood. The only effective therapy for disease is removal of a recalcitrant mixed bacterial biofilm from the tooth root surface. It is therefore believed that this biological Structure provides a constant source of bacterial antigens that stimulate the host immune system into a constant, but misdirected, non-efficacious, and destructive inflammatory response. Lipopolysaccharide (LPS) obtained from Escherichia coli is a well known potent activator of the host inflammatory system and therefore it is reasonable to suspect that LPS from P. gingivalis is also an important inflammatory activator. However, early studies established and more recent studies defined that P. gingivalis LPS does not exhibit all of the inflammatory effects of E. coli LPS. Specifically, human endothelial cells do not express E selectin nor secrete IL-8 in response to P. gingivalis LPS. Furthermore, P. gingivalis LPS blocks the endothelial cell E selectin and IL-8 response to LPS obtained from E. coli as well as bacteria found in dental plaque. In the periodontium, where bacterial exposure is constant, we propose that P. gingivalis LPS interference with the innate host inflammatory response is a critical component of the disease process. In this proposal, Specific Aim 1 examines the structural components of P. gingivalis LPS necessary for E selectin inhibition. Specific Aim 2 will determine the effects of P. gingivalis LPS on the endothelial cell activation response to E. coli LPS, and Specific Aim 3 will examine the physical interaction of both P. gingivalis and E. coli LPS with endothelial cells. Understanding endothelial cell antagonism at the molecular level will identify new therapeutic targets for intervention in periodontitis. The overall goal of this application is to identify new therapies based upon this unique virulence characteristic of P. gingivalis LPS.